Cardiovascular-Specific Mortality among Gastrointestinal Stromal Tumor Patients: A Population-Based Analysis

Background The overall risk of cardiovascular mortality (CVM) in cancer survivors has increased with time. The trend of CVM in patients with gastrointestinal stromal tumors (GISTs) remains unclear. This study is aimed at assessing the risks and independent predictors of CVM in GIST patients. Methods Data of the GIST patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019). The standardized mortality ratio (SMR) was used to evaluate the risk of CVM, and a multivariate competing risk model was utilized to identify the predictors for CVM. Results A total of 12,058 patients with GIST were included in this study, of whom 477 (4.0%) patients died of cardiovascular disease (CVD). The SMR for CVM among GIST patients was significantly higher than in the general population (SMR, 3.23, 95% CI: 2.97-3.52), and all categories of CVD were associated with a significantly elevated SMR. The cumulative mortality of CVD was the lowest among all causes of death, while the CVM was the second most common cause of death in patients ≥ 80 years when stratified by age at diagnosis. Furthermore, male sex, older age at diagnosis, White race, unmarried, earlier year of diagnosis, and not receiving chemotherapy were the poor prognostic factors for CVM. Conclusions The CVM risk in GIST patients was significantly higher relative to the general US population. Timely screening and cardioprotective interventions should be implemented to prevent the occurrence of CVM in patients with GIST.


Introduction
Gastrointestinal stromal tumors (GISTs) are the most common malignant subepithelial lesions of the gastrointestinal (GI) tract. Most GISTs originate from Cajal cells, which are the pacemaker cells of the GI tract. GISTs can occur in any part of the GI tract, but most are located in the stomach or small intestine [1,2]. With advancements in diagnostic technologies, the incidence of GISTs has been increasing steadily over the last few decades, with a global incidence of 10-15 cases per million [3,4]. The introduction of imatinib and other tyrosine kinase inhibitors as therapies has resulted in considerable increases in overall and progression-free survival in patients with GISTs, with 5-year overall and cause-specific survival rates of 74% and 82%, respectively [5][6][7][8].
As life expectancy and cancer survival rates increase, the population of cancer survivors is steadily increasing. As previously reported, the overall risk of cardiovascular disease (CVD) in cancer survivors has increased with time [9][10][11][12]. Oh et al. reported a 20-fold increase in cardiovascular mortality (CVM) in cancer patients from 2000 to 2016 in Korea [13]. The risk of CVM in gastroenteropancreatic neuroendocrine neoplasm patients was 1.2 times higher than that in the general US population [14]. Felix et al. demonstrated that the risk of CVM in endometrial cancer patients was 8.8-fold higher compared to women in the general population [15].
Given that there was no study evaluating the risk of CVM in patients with GIST, the aims of our study were to describe cause-specific mortality rates and identify independent predictors of CVM in GIST patients based on the data from the largest database. We expect that results from our study will emphasize the need to intervene early in CVD and thereby further improve survival rates in patients with GIST.

Study Population.
We collected patients diagnosed with the first primary GIST identified by the primary sites esophagus, stomach, small intestine, colon, rectum, appendix, and peritoneum and histologic code "8935/3." Patient selection is outlined in Figure 1.

Study Variables and
Outcomes. Patient demographics and clinical characteristics, including age at diagnosis, race, sex, primary tumor site, year of diagnosis, marital status, SEER stage, surgery, chemotherapy, radiotherapy, cause of death, survival time, and outcome, were extracted. The survival time was calculated as the time from the diagnosis of cancer to death of the patient due to any cause or to the last follow-up.

Statistical
Analysis. The risk of CVM for GIST patients was compared to that of the US general residents, and the results were presented as the SMR. SMR was calculated as the ratio of the observed deaths to the expected death via SEER * Stat software. The Poisson exact method was used to compute the 95% confidence interval (CI) and corresponding p values for the SMR. Fine and Gray's competing risk regression was performed to account for the two competing events: CVM and non-CVD deaths, and the crude cumulative mortality function was used to express the probability of developing primary and competing events. Multivariate competing risk survival analyses were performed to identify independent predictors of CVM. All analyses were performed using R software (version 4.1.0). A 2-sided p value < 0.05 was considered statistically significant.    Tables 1 and 2. 3.2. Comparison of CVM in Study Participants versus the General Population. The SMR for CVM among GIST patients was 3.23 (95% CI: 2.97-3.52) ( Table 1). In the subgroup analysis stratified by different clinical characteristics, the patients with a primary site in the stomach, small intestine, or rectum and no history of radiotherapy had significantly elevated SMRs relative to the general US population, regardless of sex, age at diagnosis, race, marital status, year of diagnosis, stage, surgery, and chemotherapy.

Results
SMRs specific to different categories of CVM are illustrated in Table 2. Overall, patients with GIST had a higher risk of death from CVD than the general population. The highest SMR was seen in the category of other diseases of the arteries, arterioles, and capillaries (SMR, 10.35, 95% CI: 2.82-26.49), followed by aortic aneurysm and dissection (SMR, 3.58, 95% CI: 1.54-7.04) and cerebrovascular diseases (SMR, 3.28, 95% CI: 2.62-4.04).

Cumulative Mortality of CVD.
The results from the Fine-Gray model of competitive risk used to assess cumulative mortality for all causes of death in GIST patients are shown in Figure 2(a). The cumulative mortalities for GIST, CVD, other cancer, and other noncancer diseases at 200 months of followup were 32.08%, 9.55%, 11.83%, and 11.22%, respectively. The cumulative mortality of diseases of the heart (7.17%) was the highest, followed by cerebrovascular diseases (1.84%) and hypertension without heart disease (0.34%) at 200 months of follow-up (Figure 2(b)). Figure 3 showed the cumulative mortality stratified by age at diagnosis. The cumulative mortality of CVD increased gradually with age at diagnosis and reached a plateau at approximately 200 months of follow-up. The cumulative mortality of CVD was the lowest among all causes of death when age < 80 years (Figures 3(a)-3(c)), while the cumulative mortality of CVD exceeded that of other cancer and other noncancer deaths in the oldest group (≥80 years) (Figure 3(d)). All patients were stratified by primary site (Figure 4), and the results suggested that esophageal and rectal patients had the highest (17.99%) and lowest (7.22%) cumulative mortality of CVD, respectively (Table S2).

Predictors of CVM.
We performed a multivariate competing risk analysis to identify the independent predictors of CVM in GIST patients, and the results are shown in Table 3. Female sex (hazard ratio (HR): 0.803, 95% CI: 0.682-0.947) was independently associated with lower risks of CVM. CVM in GIST patients increased as patients' age

Discussion
To the best of our knowledge, this is the first large population-based study to determine the risk of CVD in GIST patients and to identify the predictive factors of CVM in this population. Our results showed that 477 (4.0%) GIST patients diagnosed from 2000 to 2019 died of CVD, and the risk of CVM was 3.23 (95% CI: 2.97-3.52) times that of the general US population. According to the competing risk analysis, we found that the cumulative    Oxidative Medicine and Cellular Longevity mortality of CVD was the lowest among all possible causes of death involved. The cumulative mortality of diseases of the heart ranked first among the categories of CVD during the follow-up period. In addition, we identified sex, age at diagnosis, race, marital status, year of diagnosis, and chemotherapy as independent predictors of CVM in GIST patients. GISTs are largely caused by varying molecular changes in the tyrosine kinase receptor KIT or platelet-derived growth 7 Oxidative Medicine and Cellular Longevity factor receptor-α (PDGFRA); the former is considered the "classic GIST" and comprises 75% of GISTs, and the latter is the second most common type and comprises 10% of all cases. Patients with KIT or PDGFRA mutations are sensitive to the tyrosine kinase inhibitor imatinib, which was approved by the FDA in 2002 [4,18]. Over the past decade, imatinib has been evaluated in several randomized trials and resulted in overall survival benefits in completely resected or metastatic GIST patients [19][20][21]. Worryingly, imatinib has been reported to have cardiac toxicities [22][23][24]. Accordingly, we found that patients who underwent chemotherapy had a higher SMR (SMR, 4.77, 95% CI: 4.10-5.54) than those in the general US population. However, information regarding details of the chemotherapy are not available in the SEER database, and therefore, further investigation is required to clarify the contribution of specific chemotherapy to CVM.
In terms of the year of diagnosis, our study showed that the HRs of CVM for patients diagnosed with GIST in 2000-2004, 2005-2009, 2010-2014, and 2015-2019 decreased consistently across time. The key factor underlying this finding might be that advances in imaging techniques and biomarkers in cardiovascular disease enabled earlier detection and intervention [25]. In addition, thalidomide and metformin have been shown to have potential cardioprotective effects, preventing the cardiotoxicity of chemotherapeutic agents at the human and animal levels [26,27].
In the present study, we found that the cumulative mortality of CVD increased with patient age at diagnosis and accounted for the second most common cause of death in the oldest age group (≥80 years). Furthermore, multivariate competing risk analysis suggested that patients diagnosed at an older age were predisposed to die due to CVD (HR: 54.817, 95% CI: 27.075-110.985). Interestingly, the SMR of CVM was the highest when patients aged 18-49 (SMR, 15.91, 95% CI: 9.19-27.53), similar to the results reported by Sun et al. [14]. We hypothesized that older patients were likely to suffer from worse overall health, decreased immunity, and increased comorbidities such as infection [28], so they might not have a sufficient life expectancy to develop and die of CVD. In addition, we observed that male or unmarried patients had a high probability of CVM compared to controls, which might be due to worse personal lifestyle habits and worse socioeconomic status, as previous studies have proven that smoking, drinking, or living alone play an important role in the development of CVD [29][30][31].
Our study has some limitations. First, this study was a retrospective analysis of a large database from the US general population, and potential selection bias could not be eliminated, although we used strict screening criteria. Second, the mitotic index, genetic mutations, personal life history of alcohol and tobacco use, and subgrouping the no/unknown group for the radiotherapy and chemotherapy data were not available in the SEER database. In addition, there is a small amount of missing data for certain parameters.

Conclusions
In summary, our study demonstrates that the SMR of CVM in GIST patients was 3.23 times higher than that of the general US population, and all categories of CVD were associated with a significantly elevated SMR, of whom the cumulative mortality of diseases of the heart ranked first. Competing risk analysis identified sex, age at diagnosis, race, marital status, year of diagnosis, and chemotherapy as independent predictors of CVM in GIST patients. This research has provided evidence for timely screening for CVD in patients with GIST and insight to help clinicians make informed decisions about which GIST patients warrant long-term monitoring for the prevention of CVM.

Data Availability
The datasets used and/or analyzed during the current study are available from the SEER database freely or the corresponding author on reasonable request.

Disclosure
The funding body had no part in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.